Persistent, untreatable pain remains a common complication of spinal cord injury (SCI). 60% of patients with spinal cord injury will develop some form of chronic pain and more than half are refractory to treatment. The treatments and intractable pain often lead to secondary problems, including increased drug consumption, addiction and depression. Mechanisms behind the development of chronic pain remain obscure, as well as reasons why opioids lose their effectiveness in these patients. Using a rat model of contusive SCI, we found that behavioral indications of chronic pain correlate with increased spontaneous activity in nociceptors (both in vitro and in vivo), and that selective elimination of nociceptor hyperactivity reverses evoked and spontaneous pain measures. In addition, our laboratories have shown that i) functional alterations in sensory neurons from the dorsal root ganglia (DRG) play a major role in developing and maintaining post-SCI chronic pain, ii) increased activity of pain-related C-fibers impairs functional motor recovery after SCI, iii) neurons within the DRG become resistant after SCI to the inhibitory G protein Gi, a core component of opioid signaling, potentially explaining the limited effectiveness of morphine for SCI patients, and finally iv) treatment with opioids immediately after SCI undermines motor recovery and increases the likelihood of opioid dependence. Importantly, preliminary in vitro data shows that opioid insensitivity of nociceptors can be induced, not only by SCI, but also by overnight exposure to neurotrophic factors which can be elevated after SCI. We suggest that elevated neurotrophic factors contribute to development of opioid insensitivity and chronic pain. Therefore, we hypothesize that the resistance to opioids and pain sensitization of DRG neurons, and ultimately opioid dependence, is actively induced by factors released after SCI as part of the physiological response to tissue injury. Targeted inhibition of these signals may provide a useful approach to restoring responses to endogenous opioids and pain medications while blocking the development of chronic pain. Three aims will address the mechanisms leading to pain and addiction behaviors. Aim 1 will identify mechanisms that promote opioid resistance in cultured nociceptors. Aim 2 will determine if acute administration of neurotrophic factors in vivo promotes opioid resistance and dependency, while aim 3 will examine the use of neurotrophic factor inhibitors to block cellular and behavioral indices of opioid resistance, addiction, and chronic pain after SCI. (CHN: SCIRTS chn:wdg)